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Purpose To investigate the temporal and spatial infiltration of TRAMP-C1 tumors by myeloid-derived suppressor cells (MDSCs) after high-dose radiation therapy (RT), and to explore their effect on tumor growth. Methods and Materials TRAMP-C1 intramuscularly tumors were irradiated with a single dose of 8 Gy or 25 Gy. The dynamics of infiltrated MDSCs and their intratumoral spatial distribution were assessed by immunohistochemistry and flow cytometry. Cytokine levels in the blood and tumor were analyzed by multiplex immunoassay. Mice were injected with anti-Gr-1 antibody to determine whether MDSCs affect tumor growth after RT. Results CD11b+Gr-1+ MDSCs infiltrated TRAMP-C1 tumors irradiated with 25 Gy, but not 8 Gy, within 4 hours and recruitment persisted for at least 2 weeks. Both CD11b+Ly6G+Ly6C+ polymorphonuclear-MDSCs (PMN-MDSCs) and CD11b+Ly6G-Ly6Chi monocytic-MDSCs (M-MDSCs) were involved. Tumor RT also increased the representation of both MDSC subpopulations in the spleen and peripheral blood. Levels of multiple cytokines were increased in the tumors at 2 weeks, including GM-CSF, G-CSF, CCL-3, CCL-5, CXCL-5, IL-6, IL-17α, and VEGF-a; while G-CSF, IL-6, and TNF-α levels increased in the blood. PMN-MDSCs aggregated in the central necrotic region of the irradiated tumors over time, where they were associated with avascular hypoxia (CD31-PIMO+). MDSCs expressed the proangiogenic factor, matrix metalloproteinase-9, and, within the necrotic area, high levels of arginase-1 and indoleamine 2,3-dioxygenase. Depletion of PMN-MDSCs by Gr-1 antibody increased the efficacy of high-dose RT. Conclusions PMN-MDSCs infiltrate TRAMP-C1 tumors after high-dose RT. Their spatial distribution suggests they are involved in the evolution of an intratumoral state of necrosis associated with avascular hypoxia, and their phenotype is consistent with them being immunosuppressive. They appear to promote tumor growth after RT, making them a prime therapeutic target for therapeutic intervention. Assessment of MDSCs and cytokine levels in blood could be an index of the need for such an intervention.

PURPOSE To identify predictors of radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) treated with proton beam therapy (PBT). METHODS This multicenter study included 136 patients with HCC (eastern, n = 102; western, n = 34) without evidence of intrahepatic tumor progression after PBT. The RILD was defined as ascites with alkaline-phosphatase abnormality, grade ≥3 hepatic toxicity, or Child-Pugh score worsening by ≥2 within 4 months after PBT completion. The proton doses were converted to equivalent doses in 2-GyE fractions. The unirradiated liver volume (ULV) was defined as the absolute liver volume (LV) receiving

The microvasculature of a tumor plays an important role in its response to radiation therapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and blood oxygen level-dependent (BOLD) MRI are both sensitive to vascular characteristics. The present study proposed a partial irradiation approach to a xenograft tumor to investigate the intratumoral response to radiation therapy using DCE and BOLD MRI.TRAMP-C1 tumors were grown in C57BL/6J mice. Partial irradiation was performed on the distal half of the tumor with a single dose of 15 Gy. DCE MRI was performed to derive the endothelium transfer constant, K(trans), using pharmacokinetic analysis. BOLD MRI was performed using quantitative R2 measurements with carbogen breathing. The histology of the tumor was analyzed using hematoxylin and eosin staining and CD31 staining to detect endothelial cells. The differences between the irradiated and nonirradiated regions of the tumor were assessed using K(trans) values, ΔR2 values in response to carbogen and microvascular density (MVD) measurements.A significantly increased K(trans) and reduced BOLD response to carbogen were found in the irradiated region of the tumor compared with the nonirradiated region (P.05). Histologic analysis showed a significant aggregation of giant cells and a reduced MVD in the irradiated region of the tumor. The radiation-induced difference in the BOLD response was associated with differences in MVD and K(trans).We demonstrated that DCE MRI and carbogen-challenge BOLD MRI can detect differential responses within a tumor that may potentially serve as noninvasive imaging biomarkers to detect microvascular changes in response to radiation therapy.

Purpose To study the prognostic value of human papillomavirus (HPV) genotypes in patients with advanced cervical cancer treated with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT). Methods and Materials Between August 1993 and May 2000, 327 patients with advanced squamous cell carcinoma of the cervix (International Federation of Gynecology and Obstetrics stage III/IVA or stage IIB with positive lymph nodes) were eligible for this study. HPV genotypes were determined using the Easychip® HPV genechip. Outcomes were analyzed using Kaplan-Meier survival analysis and the Cox proportional hazards model. Results We detected 22 HPV genotypes in 323 (98.8%) patients. The leading 4 types were HPV16, 58, 18, and 33. The 5-year overall and disease-specific survival estimates for the entire cohort were 41.9% and 51.4%, respectively. CCRT improved the 5-year disease-specific survival by an absolute 9.8%, but this was not statistically significant ( P =.089). There was a significant improvement in disease-specific survival in the CCRT group for HPV18-positive (60.9% vs 30.4%, P =.019) and HPV58-positive (69.3% vs 48.9%, P =.026) patients compared with the RT alone group. In contrast, the differences in survival with CCRT compared with RT alone in the HPV16-positive and HPV-33 positive subgroups were not statistically significant ( P =.86 and P =.53, respectively). An improved disease-specific survival was observed for CCRT treated patients infected with both HPV16 and HPV18, but these differenced also were not statistically significant. Conclusions The HPV genotype may be a useful predictive factor for the effect of CCRT in patients with advanced squamous cell carcinoma of the cervix. Verifying these results in prospective trials could have an impact on tailoring future treatment based on HPV genotype.

Purpose To investigate whether changes in the volume transfer coefficient (K trans ) in a growing tumor could be used as a surrogate marker for predicting tumor responses to radiation therapy (RT) and chemotherapy (CT). Methods and Materials Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was consecutively performed on tumor-bearing mice, and temporal and spatial changes of K trans values were measured along with tumor growth. Tumor responses to RT and CT were studied before and after observed changes in K trans values with time. Results Dynamic changes with an initial increase and subsequent decline in K trans values were found to be associated with tumor growth. When each tumor was divided into core and peripheral regions, the K trans decline was greater in core, although neither vascular structure or necrosis could be linked to this spatial difference. Tumor responses to RT were worse if applied after the decline of K trans , and there was less drug distribution and cell death in the tumor core after CT. Conclusion The K trans value in growing tumors, reflecting the changes of tumor microenvironment and vascular function, is strongly associated with tumor responses to RT and CT and could be a potential surrogate marker for predicting the tumor response to these treatments.

Purpose To study the outcomes of patients with adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix primarily treated with radiotherapy (RT), identify the prognostic factors, and evaluate the efficacy of concurrent chemoradiotherapy (CCRT) or salvage surgery. Methods and Materials A total of 148 patients with Stage I-IVA AC/ASC of cervix after full-course definitive RT were included. Of the 148 patients, 77% had advanced stage disease. Treatment failure was categorized as either distant or local failure. Local failure was further separated into persistent tumor or local relapse after complete remission. The effectiveness of CCRT with cisplatin and/or paclitaxel was examined, and the surgical salvage rate for local failure was reviewed. Results The 5-year relapse-free survival rate was 68%, 38%, 49%, 30%, and 0% for those with Stage IB/IIA nonbulky, IB/IIA bulky, IIB, III, and IVA disease, respectively, and appeared inferior to that of those with squamous cell carcinoma of the cervix treated using the same RT protocol. Incomplete tumor regression after RT, a low hemoglobin level, and positive lymph node metastasis were independent poor prognostic factors for relapse-free survival. CCRT with weekly cisplatinum did not improve the outcome for our AC/ASC patients. Salvage surgery rescued 30% of patients with persistent disease. Conclusion Patients with AC/ASC of the cervix primarily treated with RT had inferior outcomes compared to those with squamous cell carcinoma. Incomplete tumor regression after RT was the most important prognostic factor for local failure. Salvage surgery for patients with persistent tumor should be encouraged for selected patients. Our results did not demonstrate a benefit of CCRT with cisplatin for this disease.

Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1–2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo .

Purpose: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I–IIA cervical cancer patients. Methods and Materials: A total of 228 Stage I–IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30–50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. Results: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (≥4 cm) and non-squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, ≤50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I–V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP-PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications ( p = 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP-PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone. Conclusion: Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I–IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients.

Purpose: To evaluate the clinical features of isolated paraaortic lymph node (PALN) recurrence after definitive radiotherapy, and analyze the prognostic factors and effect of salvage treatment. Methods and Materials: Of a total 876 patients who received pelvic radiotherapy after the diagnosis of primary cervical carcinoma, 26 were found to have isolated PALN recurrence as the first recurrent site, and these patients enrolled in this study. Only those with primary-site carcinoma controlled and who were free of other distant metastases were eligible. Nineteen of the 26 patients accepted salvage therapy. Fourteen patients accepted concurrent chemoradiation (CCRT), 1 accepted radiation to the paraaortic region, and 4 accepted chemotherapy alone. Clinical parameters evaluated included tumor markers (SCC and CEA) and image studies. Results: Seven of the 26 patients were alive and disease-free. All 7 survivors had salvage treatment with radiation to the paraaortic region and concurrent cisplatin-based chemotherapy. None of the patients receiving chemotherapy or radiation alone enjoyed long-term, disease-free survival. The 5-year survival rate for isolated PALN recurrence of the 14 patients who accepted salvage concurrent chemoradiation (CCRT) was 51.2%. The presence of a clinical symptom at the time of PALN recurrence was analyzed. Seven of the 12 asymptomatic patients and none of the 14 symptomatic patients survived without disease after salvage treatment. The SCC levels at recurrence showed a statistically significant relationship to disease-free survival. Conclusions: An SCC level of ≤ 4 ng/ml and a lack of symptoms at the time of recurrence were good prognostic factors in isolated PALN recurrence after primary radiation therapy. In addition to concurrent CCRT, periodical surveillance with tumor markers and imaging studies allowed early detection and salvage of those patients.

Purpose To investigate vascular responses during fractionated radiation therapy (F-RT) and the effects of targeting pericytes or bone marrow-derived cells (BMDCs) on the efficacy of F-RT. Methods and Materials Murine prostate TRAMP-C1 tumors were grown in control mice or mice transplanted with green fluorescent protein-tagged bone marrow (GFP-BM), and irradiated with 60 Gy in 15 fractions. Mice were also treated with gefitinib (an epidermal growth factor receptor inhibitor) or AMD3100 (a CXCR4 antagonist) to examine the effects of combination treatment. The responses of tumor vasculatures to these treatments and changes of tumor microenvironment were assessed. Results After F-RT, the tumor microvascular density (MVD) was reduced; however, the surviving vessels were dilated, incorporated with GFP-positive cells, tightly adhered to pericytes, and well perfused with Hoechst 33342, suggesting a more mature structure formed primarily via vasculogenesis. Although the gefitinib+F-RT combination affected the vascular structure by dissociating pericytes from the vascular wall, it did not further delay tumor growth. These tumors had higher MVD and better vascular perfusion function, leading to less hypoxia and tumor necrosis. By contrast, the AMD3100+F-RT combination significantly enhanced tumor growth delay more than F-RT alone, and these tumors had lower MVD and poorer vascular perfusion function, resulting in increased hypoxia. These tumor vessels were rarely covered by pericytes and free of GFP-positive cells. Conclusions Vasculogenesis is a major mechanism for tumor vessel survival during F-RT. Complex interactions occur between vessel-targeting agents and F-RT, and a synergistic effect may not always exist. To enhance F-RT, using CXCR4 inhibitor to block BM cell influx and the vasculogenesis process is a better strategy than targeting pericytes by epidermal growth factor receptor inhibitor.

Purpose To compare clinical behaviors and treatment outcomes between patients with squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix treated with radical hysterectomy (RH) and adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). Methods and Materials A total of 318 Stage IB–IIB cervical cancer patients, 202 (63.5%) with SCC and 116 (36.5%) with AC/ASC, treated by RH and adjuvant RT/CCRT, were included. The indications for RT/CCRT were deep stromal invasion, positive resection margin, parametrial invasion, or lymph node (LN) metastasis. Postoperative CCRT was administered in 65 SCC patients (32%) and 80 AC/ASC patients (69%). Patients with presence of parametrial invasion or LN metastasis were stratified into a high-risk group, and the rest into an intermediate-risk group. The patterns of failure and factors influencing survival were evaluated. Results The treatment failed in 39 SCC patients (19.3%) and 39 AC/ASC patients (33.6%). The 5-year relapse-free survival rates for SCC and AC/ASC patients were 83.4% and 66.5%, respectively ( p = 0.000). Distant metastasis was the major failure pattern in both groups. After multivariate analysis, prognostic factors for local recurrence included younger age, parametrial invasion, AC/ASC histology, and positive resection margin; for distant recurrence they included parametrial invasion, LN metastasis, and AC/ASC histology. Compared with SCC patients, those with AC/ASC had higher local relapse rates for the intermediate-risk group but a higher distant metastasis rate for the high-risk group. Postoperative CCRT tended to improve survival for intermediate-risk but not for high-risk AC/ASC patients. Conclusions Adenocarcinoma/adenosquamous carcinoma is an independent prognostic factor for cervical cancer patients treated by RH and postoperative RT. Concurrent chemoradiotherapy could improve survival for intermediate-risk, but not necessarily high-risk, AC/ASC patients.

Purpose To investigate vasculatures and microenvironment in tumors growing from preirradiated tissues (pre-IR tumors) and study the vascular responses of pre-IR tumors to radiation and antiangiogenic therapy. Methods and Materials Transgenic adenocarcinoma of the mouse prostate C1 tumors were implanted into unirradiated or preirradiated tissues and examined for vascularity, hypoxia, and tumor-associated macrophage (TAM) infiltrates by immunohistochemistry. The origin of tumor endothelial cells was studied by green fluorescent protein–tagged bone marrow (GFP-BM) transplantation. The response of tumor endothelial cells to radiation and antiangiogenic agent was evaluated by apoptotic assay. Results The pre-IR tumors had obvious tumor bed effects (TBE), with slower growth rate, lower microvascular density (MVD), and more necrotic and hypoxic fraction compared with control tumors. The vessels were dilated, tightly adhered with pericytes, and incorporated with transplanted GFP-BM cells. In addition, hypoxic regions became aggregated with TAM. As pre-IR tumors developed, the TBE was overcome at the tumor edge where the MVD increased, TAM did not aggregate, and the GFP-BM cells did not incorporate into the vessels. The vessels at tumor edge were more sensitive to the following ionizing radiation and antiangiogenic agent than those in the central low MVD regions. Conclusions This study demonstrates that vasculatures in regions with TBE are mainly formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Tumor bed effects could be overcome at the edge of larger tumors, but where vasculatures are formed by angiogenesis and sensitive to both treatments. Vasculatures formed by vasculogenesis should be the crucial target for the treatment of recurrent tumors after radiotherapy.

Purpose To study the prognostic value of the human papillomavirus (HPV) genotypes in cervical cancer patients undergoing radiotherapy. Patients and Methods A total of 1,010 patients with cervical cancer after radiotherapy between 1993 and 2000 were eligible for this study. The HPV genotypes were determined by a genechip, which detects 38 types of HPV. The patient characteristics and treatment outcomes were analyzed using the Cox regression hazard model and classification and regression tree decision tree method. Results A total of 25 genotypes of HPV were detected in 992 specimens (98.2%). The leading 8 types were HPV16, 58, 18, 33, 52, 39, 31, and 45. These types belong to two high-risk HPV species: alpha-7 (HPV18, 39, 45) and alpha-9 (HPV16, 31, 33, 52, 58). Three HPV-based risk groups, which were independent of established prognostic factors, such as International Federation of Gynecology and Obstetrics stage, age, pathologic features, squamous cell carcinoma antigen, and lymph node metastasis, were associated with the survival outcomes. The high-risk group consisted of the patients without HPV infection or the ones infected with the alpha-7 species only. Patients co-infected with the alpha-7 and alpha-9 species belonged to the medium-risk group, and the others were included in the low-risk group. Conclusion The results of the present study have confirmed the prognostic value of HPV genotypes in cervical cancer treated with radiotherapy. The different effect of the alpha-7 and alpha-9 species on the radiation response deserves additional exploration.

To identify prognostic factors for local and distant relapse and perform risk stratification for patients with advanced cervical cancer treated with radiotherapy (RT) alone.A total of 1031 patients with Stage IB-IVA squamous cell carcinoma of the cervix treated with full-course RT but without any chemotherapy were included for analysis. Of these, 311 patients with nonbulky Stage IB-IIA disease were designated the reference group and the other 720 patients were the study group. The associations of stage, squamous cell carcinoma antigen (SCC-ag) level, hemoglobin level, age, cell differentiation, and pelvic lymph node status with treatment failure were evaluated. The independent prognostic factors were identified by multivariate analysis. The study group was further stratified into subgroups using combinations of these risk factors.In the study group, independent risk factors for local relapse were advanced stage and age45 years. The 5-year local relapse-free survival rate was 86% for patientsor =45 years with bulky Stage IB-IIA or IIB disease, and was even greater, up to 90% if the SCC-ag level was2. In contrast, it was 65% for patients with Stage IIIB who were45 years old. The independent risk factors for distant failure were advanced stage, SCC-ag level2, and positive pelvic lymph nodes. The 5-year distant relapse-free survival rate was 83% for patients with bulky Stage IB-IIA and IIB disease, SCC-ag level2, and negative lymph nodes and 43% for patients with Stage III, SCC-ag level2, and positive lymph nodes.The risk of treatment failure in advanced-stage cervical cancer patients treated by RT alone can be more precisely predicted by risk stratification. A certain subgroup of patients had better control than the others. The benefit of treating these relatively low-risk patients with additional treatment such as concurrent chemotherapy should be further evaluated in prospective studies or meta-analyses.

To study retrospectively the characteristics and survival of patients with recurrent squamous cell carcinoma (SCC) of the cervix after definitive radiotherapy (RT) and to identify subsets of patients who might benefit from aggressive salvage treatment.Between 1990 and 1999, 1292 patients with Stage I-IVA SCC of the cervix underwent full-course RT. Of the 1292 patients, 375 (29%) had either local or distant failure and were included in this analysis. The 35 patients (2.7%) with both pelvic and distant relapse were excluded. In the 162 patients with local failure, 71 (44%) had persistent disease and 91 (56%) had a relapse after complete tumor regression. Of these 162 patients, 47 (29%) received salvage surgery. In the 213 patients with distant failure, 46 (22%) had isolated para-aortic lymph node (PALN) metastasis, and 35 (76%) of them were treated with concurrent chemoradiotherapy/RT. Patients with supraclavicular lymph node (SCLN) relapse usually underwent concurrent chemoradiotherapy. Palliative chemotherapy and/or RT were given by decision of the responsible attending physician.The independent prognostic factors for local failure were advanced stage and young age (45 years) and, for distant failure, were advanced stage, positive pelvic lymph nodes, and high serum SCC-antigen levels. The 5-year overall survival rate was 10% and 11%, respectively, for patients with local or distant failure. For local relapse, the 5-year overall survival rate was 29% vs. 3% (p = 0.0001) for patients with vs. without salvage surgery and 22% vs. 9% vs. 4% for patients with tumors confined to the cervix, tumors extending but not beyond the cervix and adjacent tissues, and tumor extending beyond adjacent tissues but contained within the pelvis (p = 0.005). The survival rates, either with or without salvage surgery, were nearly identical between patients with persistent disease and those with relapse after complete regression. The 3-year overall survival rate was 34%, 28%, and 5% (p = 0.001), respectively, for patients with PALN relapse alone, SCLN relapse with or without PALN relapse, and relapse other than PALN and SCLN. Of the patients with PALN relapse alone, 27% survived5 years.For recurrent SCC of the cervix after RT, patients with isolated PALN relapse salvaged by RT or combined chemoradiotherapy or those with cervical relapse salvaged by surgery can achieve long-term survival. Early detection of relapse with aggressive salvage treatment is important for achieving better outcome. Patients with persistent disease or relapse after complete remission had similar outcomes. Patients with SCLN relapse had a longer survival time than those with other metastases (except PALN), and palliative RT might be beneficial.

Purpose: To investigate the prognostic significance of the pre- and posttreatment serum squamous cell carcinoma antigen (SCC) levels in patients with Stage I-IVA squamous cell carcinoma of the cervix primarily treated by radiotherapy. Materials and Methods: 401 patients with squamous cell carcinoma of cervix primarily treated with radiotherapy (RT) were included in this study. All had preRT, and 249 patients had postRT serum SCC values. The association of pretreatment SCC level with the clinical parameters, including stage, hemoglobin (Hb) level, age, cell differentiation, and lymph node status, was assessed by univariate and multivariate analysis. The prognostic significance of pretreatment SCC level and these clinical parameters were evaluated. The impact of postRT residual induration and SCC levels on survival was analyzed. Results: 1. PreRT SCC level strongly correlated with stage. After controlling for stage, only SCC levels higher than 10 ng/ml were associated with enlarged lymph nodes shown in CT scan. No association of preRT SCC level with other clinical parameters was found. 2. SCC level higher than 10 ng/ml, but not between 2–10 ng/ml, had significant impact on survival in a multivariate analysis. Stage, Hb levels (

To present the treatment results and assess the optimal radiation dose and the role of brachytherapy in early stage nasopharyngeal cancer (NPC).One hundred eighty-three patients with Stage I and II (American Joint Committee on Cancer Staging System, 1987) NPC completed the planned radiotherapy in our institution from 1979 to 1991. In 133 patients, radiotherapy was given to the nasopharynx by external beam to 64.8-68.4 Gy. Further boost was done by high dose rate (HDR) brachytherapy for 5-16.5 Gy in one to three fractions. For the remaining 50 patients, a course of external radiotherapy to the nasopharynx for 68.4-72 Gy was given to nasopharynx. Age (40 or not), sex, neck boost or not, brachytherapy, and irradiation dose were analyzed to determine significant factors that influence the probabilities of local control and actuarial survival.The 5-year disease-specific survival was 85.8% and local control was 83%. Only the brachytherapy and irradiation dose significantly affected the results. The use of the brachytherapy had significant impact on overall survival and local control. Furthermore, we compared the prognostic effect of various radiation dosage among Group I of 50 patients (72.5 Gy, no brachytherapy, excluding four patients who received brachytherapy), Group II of 71 patients (72.5-75 Gy; one to two fractions of brachytherapy), and Group III of 58 patients (75 Gy; three fractions of brachytherapy). Five-year disease-specific survival rates of Group I, Group II, and Group III were 77, 95.5, and 82.4%, respectively. Five-year local control rates were: 73.7, 93.9, and 79.5%. We found that the Group II had the best actuarial survival and local control rate (log-rank test,p0.05). Most patients receiving brachytherapy encountered foul odor because of nasopharynx crust; 12 of them had palate or sphenoid sinus floor perforation or nasopharynx necrosis. None of the patients without brachytherapy experienced the same complications.The optimal radiotherapy dose to the nasopharynx area in early stage NPC may be within 72.5 to 75 Gy by our treatment protocol. A dose of more than 75 Gy did not have significant local control or survival advantage. The use of brachytherapy to elevate radiation dose had significant local control and survival benefit for early stage NPC patients, but the fractionation size should be decreased to reduce the complications.